In this paper, we present a brief overview of topics
critical to decision making when considering pesticide screening of Cannabis consumables. We discuss the
inherent challenges faced when setting tolerance levels for any crop, as well
as challenges unique to this crop, and we describe the methods used by the EPA
and other similar agencies around the world to address those challenges. We
present a framework for establishing limits in the absence of federal oversight
which utilizes publically available toxicology data, including data made public
by the federal government, to inform its decisions. We apply this framework to
the 15 pesticides currently on the DOH's list for screening in Cannabis, and we propose that the state
of Washington adopt the following limits for pesticides residues on Cannabis:

These limits are not fixed in nature, and as such they
should not be set in stone. This is an evolving list, and as more data are
generated the list and the limits will necessarily be updated.

Background

The Washington state legal marijuana market is currently
regulated by the Washington State Liquor and Cannabis Board (WSLCB) for
recreational purposes under the Washington Administrative Code (WAC) 314-55.
New regulation, posed to come into effect in the summer of 2016, will
incorporate an extant medical marijuana market in this state into the legal
marijuana market under the purview of the WSLCB in conjunction with the
Washington state Department of Health (DOH).

The DOH has proposed new rules for medical marijuana
(WAC-246-70) that act to supplement the rules enforced by the WSLCB. Included
in these new rules are new quality assurance testing requirements including
screening for pesticides, mycotoxins, and heavy metals. While the proposed
rules describe tolerance levels for the latter two, the DOH is yet to define
tolerance levels for pesticides.

Very limited research is available to guide decision making
regarding what concentrations of pesticides should be allowed on or in cannabis
products. Marijuana producers are disallowed from using pesticides primarily
because the Environmental Protection Agency (EPA), the federal agency responsible
for approving pesticides, is unable to approve pesticide use for cannabis crops
or establish tolerance levels due to the plant's federal status as a Schedule 1
narcotic.

Cannabis industry stakeholders of Washington state are now
tasked with establishing limits without guidance from the federal agencies
typically responsible for such work. The difficulty is further compounded by
the diverse and very unique methods by which this drug is administered,
including combustion and inhalation, vaporization and inhalation, oral
consumption, dermal application, sublingual application, suppository insertion,
among others.

If the application of
pesticides is not allowed on this crop, should the tolerance limit be zero?

Setting pesticide tolerance limits of zero for crop commodities
is not appropriate. Pesticides are ubiquitous in our environment, and
detectable levels can be found nearly anywhere if you look hard enough, even in
drinking water. While we would certainly prefer not to find pesticides in our
consumables, we do cope with the fact that exposure is a daily occurrence. Pesticide drift is a term that describes the airborne
movement of pesticides away from their intended target, and that phenomena is
considered normal in the agricultural field.

Click to read more...

The EPA sets tolerance levels for pesticide-crop
combinations for one of two reasons: (1) approved direct application, (2) indirect
or inadvertent exposure.

For pesticide-crop combinations where direct application of
a pesticide is approved, toxicological data are used to determine what level of
residual pesticide on the final product is considered safe for consumption. In
this case, pesticides are being applied directly onto the plant, and we want to
be sure that the levels present on the consumable are low enough so as to not present
a measurable health risk.

Sometimes tolerance limits are also established for
pesticide-crop combinations where direct application of the pesticide is not
approved, as is the case with cannabis in Washington state. In these cases,
tolerance limits are not so much based on toxicological data, they are instead based
on the amount of pesticide residue that would indicate illegal or inadvertent application.
These limits tend to be much lower than limits set for approved use, because we
don't expect to find much of a pesticide on a plant that has not had the
pesticide directly applied. Limits for inadvertent exposure are intended to
identify cases where the pesticide has been wrongly applied or the amount of
pesticide drift occurring is more than normal and should be addressed. These
limits are never set at zero; some amount of pesticide drift is always allowed
and often expected.

Isn't smoking
pesticides more dangerous than eating them?

That is a reasonable assumption to make. Though there does not
exist much data to support that assumption, in the absence of evidence we
should err on the side of caution. It is important to consider that the danger level
presented by a pesticide exposure is influenced more by the size of the dose
than by the route of exposure. The EPA has extensively investigated risk of
exposure to pesticides from cigarette smoking [GAO] [Djordjevic],
and has used that research to set tolerance limits for 37 pesticides approved
for application on tobacco as well as 20 pesticides with tolerance limits for
inadvertent exposure. The tolerance limits established for pesticides on
tobacco are not much lower than the limits established for other crop commodities.
Even tolerance levels for highly toxic and persistent pesticides, such as Dichlorodiphenyltrichloroethane
(DDT), are not exceptionally low for tobacco (0.1 ppm). The agency justifies
this through research analyzing data on toxicity and the residue levels that
remain on tobacco and in tobacco smoke, which have generally concluded that the
low levels of residues measured in tobacco smoke are a minor source of human
exposure and do not pose health concerns that require mitigation [GAO]. The
most dangerous cases of human inhalation exposure from pesticides occur when
farm workers and farm neighbors are actively exposed to aerosolized pesticides
during and after application. The level of exposure in these cases can be quite
high and can pose a significant health risk [Lee].

How does the EPA
determine tolerance limits?

Setting pesticide tolerances on any agricultural product for
human consumption is not a simple, straight-forward, or easily referenced task.
Ideally, the risk assessment is performed individually for each crop-pesticide
combination. For sufficiently similar propositions to other approved
combinations, data acquired from previous investigations can be used [EPA-1]. The
EPA takes a multistep approach when determining recommended pesticide limits,
or tolerances. This risk assessment process is a general evaluation of ecological
or human risk from any anthropogenic environmental stressor [EPA-2]. Typically,
tolerance limits are set for pesticide-crop combinations where application of
the pesticide is approved, but sometimes limits for incidental exposure are
also defined.

Click to read more...

Below is a rough outline of the risk assessment process used
by the EPA in evaluating proposed use and establishing tolerance limits for
pesticides.

Risk Assessment Process for pesticides:

1.Pesticide Registration

2.Evaluation of pesticide toxicity and its
breakdown products

a.Hazard Identification

b.Dose-response assessment

c.Exposure assessment

d.Risk characterization

3.The involvement of other federal agencies:

a.The Food and Drug Administration (FDA) is
responsible for testing foods, both domestic and imported, for compliance to
tolerances

b.State enforcement agencies may exist to oversee
foods produced and consumed within a state

c.The United States Department of Agriculture
(USDA) is responsible for testing dairy and meat products

4.Numerous scientific studies are required to set
tolerances (validation for steps 2 and 3 above):

a.Rigorous toxicological profile of a pesticide
and its breakdown products

b.Rigorous analysis of actual exposure to
pesticide and breakdown products when the commodity is consumed (per-weight
basis)

Below, we evaluate each step in the risk assessment process
for pesticides, and comment on the implications for application of the process
to determining pesticide tolerance levels for cannabis.

1.The first item in the list above, Pesticide
Registration, is an action performed by a pesticide manufacturer. When a new
pesticide is discovered or invented, or a new use for an existing pesticide is
proposed, the would-be manufacturer registers the pesticide with the EPA and
describes the intended use, anticipated outcomes, and reports in detail what
research the manufacturer has already done. Federal prohibition of cannabis has
prevented any pesticide registration for use on cannabis crops, which is
ultimately the reason why the EPA has not devoted any resources to this topic.
In Washington state, only a limited number of pesticides are allowed in the
cultivation of cannabis crops, and these pesticides are considered safe at any
level [PICOL]. As
such, the first item on the lest above is not applicable to this paper, except
to note that the Washington state DOH does have in place a mechanism for
approving new pesticide use on Cannabis
[PICOL].

2.Evaluation of pesticide toxicity is a critical
step in the process. The EPA evaluates anticipated or known toxicity of the
pesticide and its breakdown products to humans and the environment. With
regards to environmental toxicity, special attention is given to potential
impact on endangered species and fluvial systems. Much of the data used to evaluate
ecological impact comes from field research conducted by the registrant.
Because Washington state marijuana growers are forbidden to apply pesticides
with tolerance limits, ecological impact of pesticide application on marijuana
is not relevant to this topic of discussion. Human toxicity provides its own
challenging topic to address. Ethical constrains largely prevent researchers
from experimenting directly on human subjects, so conclusions about human
toxicity are based on literature review, historical case studies, tissue
studies, animal studies, and limited human exposure trials. A dietary risk
assessment is used to estimate how much of the crop commodity a human will
consume on a regular basis. This assessment accounts for the fact that the
diets of infants and children may be quite different from those of adults and
that they consume more food for their size than adults. The following four
steps are used to assess the human health impacts of a pesticide:

a.Hazard Identification (Toxicity). The potential
for the pesticide to cause harm to humans is identified, and the circumstances
which may heighten the risk are examined. Oral, dermal, and inhalation
exposures are examined for all three of acute, sub-chronic, and chronic
exposures. Developmental and reproductive risks are also investigated.

b.Dose-Response Assessment. Paracelsus, the Swiss
physician and alchemist, the "father" of modern toxicology (1493-1541) said, "The
dose makes the poison." In other words, the amount of a substance a person is
exposed to is as important as how toxic the pesticide might be. For example,
small doses of aspirin can be beneficial to people, but at very high doses this
common medicine can be a deadly poison. In some individuals, even at very low
doses, aspirin may be deadly. Dose-response assessment examines the numerical
relationship between exposure and effects. The EPA considers the dose levels at
which harmful effects are observed in test animals, and uses those measurements
to calculate what an equal dose would be in humans.

c.Exposure Assessment. The exposure assessment
examines what is known about the frequency, timing and levels of contact with a
pesticide. Here, the agency is considering how frequently a consumer might be
consuming the commodity and in what quantity. Special considerations concerning
occupational exposure and leeching into groundwater or fluvial systems are also
taken, however, occupational and environmental considerations are not
applicable to this paper because marijuana farms should not be applying
pesticides with tolerance limits.

d.Risk Characterization. Risk characterization is
the final step in assessing human health risks from pesticides. In this step, conclusions
are drawn about the nature and extent of the risk from exposure to the
pesticide. The risk to human health from pesticide exposure depends on both the
toxicity of the pesticide and the likelihood of people coming into contact with
it. Simply put: RISK = TOXICITY x EXPOSURE

Toxicity evaluation of pesticide breakdown
products (degradation products) presents one of the greatest challenges for
evaluation of pesticides on cannabis. Many pesticides are designed to begin
breaking down once they are exposed to water, light, or air [Kamrin] [WSU]. This feature reduces the pesticide burden in
the final product and helps ensure that the product breaks down into anticipated
daughter products that are known to be of low hazard risk. This consideration
is made even more challenging for the case of cannabis by the fact that little
is known about what breakdown products will result from combustion of the
pesticides. Without knowing what breakdown products can be expected from normal
use (combustion) it is impossible to estimate the toxicity of breakdown
products. This is the primary reason why tolerance limits for pesticides in
cannabis are likely to be conservative.

3.Multiple state and federal agencies are
typically involved in setting and reviewing tolerances for pesticides. The
federal classification of cannabis as a Schedule 1 Narcotic prevents federal
agencies from involvement in this crop. That said, these agencies do supply
immense amounts of publically available data which are used in this paper to
make our own assessments [PDP] [USDA]. State agencies are also frequently involved
in monitoring and reporting about pesticides in crop commodities, and in this
state the DOH is actively involved in establishing tolerances.

4.Pesticide companies, or registrants, must submit
a wide variety of scientific studies for review before the EPA will set a
tolerance. The data are designed to identify:

a.Possible harmful effects the chemical could have
on humans (its toxicity).

b.The amount of the chemical (or breakdown
products) likely to remain in or on food.

c.Other possible sources of exposures to the
pesticide (e.g., through use in homes or other places).

In addition, there must be a
practical method for detecting and measuring levels of the pesticide residues
so regulatory officials and testing laboratories can ensure that residues in
shelf products are below the level determined to be safe. The Organization for
Economic Co-operation and Development (OECD) provides a publically available
calculator for use in the numerical portion of the tolerance-setting process [OECD].

5.Before a tolerance is set or an exemption is granted,
the public has an opportunity to comment on proposed new pesticide tolerances. A
notice is published in the Federal Register announcing the receipt of a
petition for a tolerance or exemption. The list of tolerances and exemptions is
compiled in the Code of Federal Regulations (CFR), Chapter 40, Part 180. While
these federal actions will not apply to cannabis until rescheduling of the
plant, the Washington state DOH is the acting body setting tolerances in this
state. Additionally, Washington State University is maintaining a database of
pesticides [PICOL].

Without EPA guidance,
how can state governments make informed decisions about pesticide tolerance
limits?

Such rigor as is executed by the EPA in determining
tolerances for pesticides in the Unites States does not come cheap, and is
beyond the capability of most state governments and even national governments.
That said, the process used by the EPA to evaluate pesticides is both
transparent and collaborative, enabling state and national governments to
piggyback on that same effort to establish similar -- or even more rigorous --
standards for themselves. The cannabis industry of Washington state should be
able to set reasonable pesticide tolerance limits using existing data and
precedence.

Click to read more...

In consideration of the EPA's risk assessment process
described above, establishing tolerance limits for cannabis in Washington state
is dramatically simplified by the fact that application of pesticides with
tolerance limits is prohibited. Cannabis plants grown in the legal marijuana
market for this state should not come in contact with prohibited pesticides
except inadvertently. As a result, there is not much need to consider policy
regarding the ecological impacts or occupational hazards associated with
pesticide application on cannabis except to enforce the illegality of that
application.

Ecological and occupational considerations aside, our focus
is now almost entirely on consumer hazard. The tolerance limits for pesticides
in cannabis need to be low enough to provide confidence that the hazard risk is
negligible. In this light, a conservative approach is justified. As discussed
above, toxicity evaluation regards not only the toxicity of the pesticide, but
also the toxicity of the possible breakdown products. Because the breakdown
products under conditions of combustion are unknown for many pesticides,
additional caution has been recommended for marijuana commodities where
combustion is a common route of delivery. Furthermore, because application of
these pesticides is prohibited, not only do we prefer lower pesticide burden
than is tolerated on crops where application is approved, we expect lower
burden.

In order to utilize the existing literature about pesticide
tolerances, it becomes important to make comparisons between cannabis and other
commodities. In doing so, the following considerations are important:

—
The structure of the commodity being compared to
should be similar to the structure of the cannabis commodity. For cannabis
flowers, this means comparing to a commodity composed of leaves, flowers, or
grains. Tubers would be a poor choice for comparison, as their structure and
environment are very dissimilar to cannabis. For cannabis concentrates, which
are very diverse in form, adequate comparisons are harder to come by. Powdered
caffeine presents a good comparison, as it is typically extracted with
supercritical CO2 or a solvent such as ethyl acetate, and is
consumed in very small doses on the order of milligrams [Coffee]. Citrus oil is
often extracted through pressing or distillation using methods that are now being
applied to cannabis [22].

—
The anticipated daily maximum consumption of the
commodity should be taken into account. Setting a daily intake estimate
provides one of the firmest reference points to frame the debate on
establishing pesticide tolerances, as daily cannabis consumption by even the
most cannabis-exuberant individuals is unlikely to approach their daily
consumption for food products (wheat, rice, corn, fresh produce). If the
pesticide burden (in nanograms per gram) is the same for an apple as it is for
a joint, then the apple is supplying the consumer with 250 times as much
pesticide as is the joint, because the apple weighs 250 grams while the joint
only weighs 1 gram. If the apple and the cannabis share the same tolerance
limit, that limit is more conservative for cannabis where the total biomass
consumed is much less.

—
The route of exposure is the most challenging
aspect. Cannabis commodities are fairly unique in that their route of exposure
is often inhalation following combustion and/or vaporization. For this route of
exposure, the only useful comparison is tobacco. A total of 37 pesticides are
commonly used on tobacco [GAO], and one of those 37 is on DOH's list of
pesticides to be tested for in the medical marijuana market and has tolerance
levels set for tobacco [7 CFR]. The EPA also tests imported and domestic
tobacco for some pesticides not approved for use on tobacco. Their tolerance levels
for highly toxic and persistent pesticides, such as Dichlorodiphenyltrichloroethane
(DDT), are not exceptionally low compared to other crops (0.1 ppm). The agency
justifies this through research analyzing data on their toxicity and the
residue levels that remain on tobacco and in tobacco smoke, which have
generally concluded that the low levels of residues measured in tobacco smoke are
a minor source of human exposure and do not pose health concerns that require
mitigation [GAO] [Djordjevic].

Toward the goal of providing guidance to other agencies
setting pesticide tolerance limits, the EPA website provides a very detailed
description of how that agency sets tolerances [EPA-3]. The US Government
Publishing Office provides a searchable database of federal regulations [ECFR]
as does the Legal Information Institute of Cornell University Law School [7
CFR]. The USDA's Pesticide Data provides the most comprehensive pesticide
residue database in the US [PDP], and the FDA's Pesticide Program Residue
Monitoring provides additional data [USDA]. The Pesticide Action Network's (PAN)
Pesticide Database provides detailed information about the known toxicology of
pesticides [PAN], as does Toxipedia [Toxipedia]. The National Health and Nutrition Examination
Survey (NHANES), and the EPA's resultant What We Eat in America - Food
Commodity Intake Database (WWEIA-FCID), provides data on daily human exposure
from food [WWEIA].

Have pesticide
tolerance levels ever been established for Cannabis?

Yes. Colorado, Oregon, and Nevada have all drafted
legislation that describe tolerance limits for pesticides on Cannabis, and mandate testing for pesticides
on Cannabis in at least some circumstances.
Colorado bases its tolerance limits for Cannabis on the federal tolerance limits
for tobacco [DenverPost]. Nevada bases its tolerance
limits on the most stringent acceptable standard for the pesticide residue on
any food item, as set by the EPA [NV.GOV]. The Oregon Health Authority
consulted a team of Toxicologists to set limits for Cannabis in that state [OHA]. In all of these cases, there has been
acknowledgment that more research is needed to better inform these decisions.
The states have all used different methods in determining tolerance levels, but
nonetheless have come to similar conclusions. In all states, it is important
for the laws describing tolerance limits to be subject to revision as more data
and research comes to light.

About Risk Assessment. (n.d.).
Retrieved March 19, 2016, from https://www.epa.gov/risk/about-risk-assessment

[EPA-3]

Regulation of Pesticide Residues on Food. (n.d.).
Retrieved March 21, 2016, from https://www.epa.gov/pesticide-tolerances

[GAO]

Pesticides on tobacco: Federal activities to assess risks and
monitor residues: Report to the Ranking Minority Member, Committee on
Government Reform, House of Representatives. (2003). Washington, D.C.: U.S.
General Accounting Office.